CN118831050B

CN118831050B - A 5α-reductase inhibitor alcohol-containing emulsion and its preparation method and application

Info

Publication number: CN118831050B
Application number: CN202411281626.4A
Authority: CN
Inventors: 周映聪; 刘洁秀; 雷磊; 张林东; 邹柏舟; 李常辉; 杨丽鸳; 林国钡
Original assignee: Chendi Pharmaceutical Technology Shanghai Co ltd
Current assignee: Chendi Pharmaceutical Technology Shanghai Co ltd
Priority date: 2024-09-12
Filing date: 2024-09-12
Publication date: 2025-01-28
Anticipated expiration: 2044-09-12
Also published as: CN118831050A

Abstract

The invention discloses an alcoholic emulsion of a 5α-reductase inhibitor, which comprises a 5α-reductase inhibitor, an alcohol, an oil phase, an emulsifier, a diluent and a penetration enhancer. The alcoholic emulsion of the invention not only retains the refreshing skin feel of the alcoholic preparation, but also solves the technical problem that ethanol destroys the stability of the emulsion, has excellent stability and transdermal performance, is suitable for use on the scalp, and is used for the treatment of androgenic alopecia.

Description

Alcohol-containing emulsion of 5 alpha-reductase inhibitor and preparation method and application thereof

Technical Field

The invention relates to the technical field of medicines, in particular to an alcohol-containing emulsion of a 5 alpha-reductase inhibitor, and a preparation method and application thereof.

Background

Androgenic alopecia, also known as seborrheic alopecia, is the most common progressive alopecia. The occurrence of androgenetic alopecia is closely related to the in vivo concentration of dihydrotestosterone. 5 alpha-reductase inhibitors such as finasteride and dutasteride inhibit 5 alpha-reductase activity by forming enzyme complexes, inhibit testosterone conversion to dihydrotestosterone, thereby reducing dihydrotestosterone concentration, and are effective in treating androgenic alopecia.

Commercially available 5 alpha-reductase inhibitors are mainly oral formulations for the treatment of benign prostatic hyperplasia in men or androgenic alopecia in men. The oral administration of the 5 alpha-reductase inhibitor can produce various adverse reactions such as erectile dysfunction, hyposexuality, ejaculation dysfunction, breast pain, gynecomastia, and the like, and the local external preparation can effectively reduce toxic and side effects caused by systemic exposure, thereby improving the treatment safety and patient compliance. For example, finasteride spray (trade name: CARETOPIC ^®) is used to treat male androgenic alopecia with similar clinical efficacy as oral finasteride.

Commercially available external preparations for treating alopecia generally contain ethanol, such as minoxidil tincture and minoxidil foam. After the use, the ethanol can volatilize on the scalp quickly, so that the scalp and hair are dried quickly, the skin feel is fresh and not greasy, and the use experience of patients is good. Most of the existing products are solutions, and have the defects of easy dripping, difficult uniform coating, short residence time of the medicine on the skin, limited transdermal absorption and the like when the existing products are applied to the scalp. Compared with homogeneous solution, the oil-in-water emulsion can increase solubility of insoluble drug and residence time of the preparation on skin, and micrometer-scale emulsion droplets are dispersed in continuous phase, so as to effectively improve transdermal absorption of active ingredient and reduce irritation. However, developing an alcohol-containing emulsion suitable for use on scalp sites presents a significant technical challenge. Firstly, ethanol can reduce the surface tension of an oil-water interface, so that the stability of the emulsion is damaged, and most of common emulsifying agents can be dissolved and extracted into a water phase by the ethanol and cannot be well distributed on the oil-water interface to form a stable emulsion. Second, oil-in-water emulsions typically contain 10% to 50% of the oil phase and a residual amount of water, such oil-to-water ratio being advantageous for forming a stable emulsion system. However, if the oil phase with such a high content is used on scalp, a large amount of oil phase will adhere to hair after the water phase volatilizes, and even if the oil phase ratio is as low as 10%, the oil phase will have a greasy feel, even adhere to hair, and affect medication compliance of patients. Again, topical emulsions are generally semi-solids with a high viscosity that facilitates stability of the emulsion system, but formulations for scalp areas need to be thin and light, i.e., have good flowability and spreadability to avoid sticking to the hair, but developing low viscosity and stable alcoholic emulsions presents a greater challenge.

In addition, commercially available 5 alpha-reductase inhibitors finasteride and dutasteride are high in fat solubility and poor in transdermal absorption, the preparation can achieve ideal transdermal absorption by adding a permeation enhancer, and the permeation enhancer can interact with ethanol and an emulsifying agent, so that the stability of the alcoholic emulsion is affected, and the development difficulty of the alcoholic emulsion is further increased.

Further, the main drawbacks of the prior art are the improvements that the present invention can provide:

1. The existing scalp external hair-growing medicine is almost solution type preparations, but the invention is emulsion which can provide better skin feel and use feeling than the solution, thereby improving medication compliance.

2. The dutasteride has extremely low solubility, and if the traditional solution formulation is used, the dutasteride is easy to precipitate and precipitate at low temperature so as to influence the concentration and dosage accuracy of the medicine, and the emulsion of the invention can not generate medicine crystallization precipitate even under the freezing and thawing condition, thereby greatly improving the stability in storage and use.

3. The existing emulsion type scalp external cosmetic contains no more than 20% of ethanol, because the ethanol is a demulsifier, general emulsion can be demulsified and layered after encountering the ethanol, and the emulsion contains the ethanol up to 33% -34% of ethanol, and the emulsion has the advantages that (1) the ethanol with higher concentration can improve the transdermal absorption of the medicine so as to improve the bioavailability, and (2) the ethanol with higher concentration can volatilize and dry the product after being applied to the skin, so that the wet scalp and hair can be quickly restored to a normal state without affecting the outgoing social interaction, thereby improving the medication compliance, and (3) the prescription has the antiseptic capability without adding an antiseptic or adopting other antiseptic measures.

4. In order to keep emulsion stable, the existing emulsion type external product needs to use a high percentage (usually more than 10 percent) of emulsifying agent, but the dosage of the emulsifying agent is as low as about 1.5 percent, and the less the stimulus of the emulsifying agent to the skin is, thus being very suitable for long-term daily administration of scalp.

5. Dutasteride has very poor water solubility and is practically insoluble in water, even though it has low solubility in some common solvent-type liquid excipients. However, the daily long-term scalp preparation should not contain ethanol in excess of 65%, otherwise the skin is more irritating, and the remaining percentage should be complemented to 100% by using other adjuvants, in which case, if water is used, the solubility of the drug is greatly reduced, and the "alcohol-oil" system obtained by using other liquid adjuvants which are miscible with ethanol is difficult to emulsify.

Disclosure of Invention

Based on this, the present invention provides an alcohol-containing emulsion of a 5α -reductase inhibitor comprising a 5α -reductase inhibitor, an alcohol, an oil phase, an emulsifier, a diluent, and a penetration enhancer.

Further, the alcohol-containing emulsion comprises 0.005-0.5 wt% of 5 alpha-reductase inhibitor, 20-60 wt% of alcohol, 1.0-3.0 wt% of oil phase, 1.0-3.0 wt% of emulsifier, 10-35 wt% of diluent and 5-55 wt% of penetration enhancer according to the weight percentage of the alcohol-containing emulsion.

Further, the oil phase is not in a liquid state at normal temperature.

Further, the emulsifier is not in a liquid state at normal temperature.

Further, the emulsion does not contain an oil phase that is liquid at ordinary temperature.

Further, the emulsion does not contain an emulsifier which is liquid at ordinary temperature.

Further, the 5α -reductase inhibitor comprises a scalp external hair growth medicament.

Further, the 5α -reductase inhibitor is dutasteride and/or finasteride.

Further, the alcohol-containing emulsion comprises 0.01 to 0.5wt%, further 0.02 to 0.2 wt% of 5 alpha-reductase inhibitor, based on the weight percentage of the alcohol-containing emulsion.

Further, the alcohol is ethanol, such as absolute ethanol.

Further, the alcohol-containing emulsion comprises 25 wt% to 40 wt% alcohol, such as about 33 wt%, based on the weight percentage of the alcohol-containing emulsion.

Further, the weight ratio of the alcohol to the diluent is not higher than (2.6-3.4): 1.6-2.4.

Further, the oil phase is hydrocarbon or wax which is not liquid at normal temperature.

Further, the hydrocarbon material comprises saturated alkanes and/or unsaturated alkanes having 18 or more carbon atoms per molecule.

Further, the wax substance contains oils and fats having 18 or more carbon atoms per molecule and/or solid waxes.

Further, the wax is natural or synthetic wax.

Further, the oil phase is selected from one or more of petrolatum, white beeswax and fatty alcohols having more than 18 carbon atoms.

Further, the fatty alcohol containing more than 18 carbon atoms is stearyl alcohol and/or behenyl alcohol.

Further, the alcohol-containing emulsion comprises 1 wt% to 2wt%, further 1.3 wt% to 1.8 wt%, further 1.4 wt% to 1.8 wt%, such as about 1.72 wt% of an oil phase, such as about 1.6 wt% of an oil phase, such as about 1.489 wt% of an oil phase, based on the weight percentage of the alcohol-containing emulsion.

Further, the emulsifier is selected from one or more of the group consisting of a fatty alcohol polyether, a sucrose fatty acid ester, and a sorbitol fatty acid ester.

Further, the hydrophobic end of the fatty alcohol polyether contains at least 16 carbon atoms, for example 16 to 22 carbon atoms.

Further, the hydrophilic end of the fatty alcohol polyether comprises 2 to 30 polyoxyethylene repeating units, for example, 10 to 20 polyoxyethylene repeating units.

Further, the fatty alcohol polyether is selected from one or more of the group consisting of a stearyl alcohol polyether, a cetyl alcohol polyether, and a behenyl alcohol polyether.

Further, the scleropolyether is selected from one or more of the group consisting of scleropolyether-2, scleropolyether-10, scleropolyether-20.

Further, the cetostearyl alcohol polyether is selected from one or more of cetostearyl alcohol polyether-5, cetostearyl alcohol polyether-10, cetostearyl alcohol polyether-15, cetostearyl alcohol polyether-20, cetostearyl alcohol polyether-25.

Further, the cetostearyl alcohol polyether is cetostearyl alcohol polyether-20.

Further, the sucrose fatty acid ester is sucrose stearate.

Further, the sorbitol fatty acid ester is span 60.

Further, the behenpolyether is selected from one or more of behenpolyether-5, behenpolyether-10, behenpolyether-20 and behenpolyether-30.

Further, the behenpolyether is behenpolyether-30.

Further, the behenpolyether is behenpolyether-20.

Further, the alcohol-containing emulsion comprises an oil phase and an emulsifier in a total amount of 2.5 to 6 wt%, for example 3 to 5wt%, based on the weight percentage of the alcohol-containing emulsion.

Further, the alcohol-containing emulsion comprises 0.5 wt% to 5wt%, further 1 wt% to 2.5 wt%, such as about 1.72 wt% of an oil phase, such as about 1.6 wt% of an oil phase, such as about 1.489 wt% of an oil phase, based on the weight percentage of the alcohol-containing emulsion.

Further, the alcohol-containing emulsion comprises from 1 wt% to 2 wt%, further from 1.3 wt% to 1.8 wt%, such as about 1.511 wt% of an emulsifier, such as about 1.3 wt% of an emulsifier, such as about 1.4 wt% of an emulsifier, based on the weight percent of the alcohol-containing emulsion.

Further, the weight ratio of the oil phase to the emulsifier is 1:2-5:1, and further 1:2-2:1.

Further, the weight ratio of the cetostearyl alcohol polyether-20 to the behenyl alcohol polyether-20 is 1:1-10:1, and further 1:1-7:1.

Further, the alcohol-containing emulsion comprises from 0.5 wt.% to 2.0 wt.%, further from 0.8 wt.% to 1.4 wt.%, such as about 1.254 wt.% of cetostearyl alcohol polyether-20, such as about 1.117 wt.% of cetostearyl alcohol polyether-20, such as about 1.03 wt.% of cetostearyl alcohol polyether-20, based on the weight percent of the alcohol-containing emulsion.

Further, the alcohol-containing emulsion comprises 0.1 wt% to 0.8 wt%, further 0.2 wt% to 0.6 wt%, such as about 0.257 wt% behenyl polyether-20, such as about 0.283 wt% behenyl polyether-20, such as about 0.414 wt% behenyl polyether-20, based on the weight percent of the alcohol-containing emulsion.

Further, the diluent is water, such as purified water.

Further, the alcohol-containing emulsion comprises 15 wt% to 30 wt%, such as about 23 wt% water, based on the weight percent of the alcohol-containing emulsion.

Further, the permeation enhancer is diethylene glycol monoethyl ether and/or propylene glycol.

Further, the alcohol-containing emulsion comprises 10 to 50 wt%, further 30 to 50 wt%, such as about 40 wt%, of the penetration enhancer, based on the weight percentage of the alcohol-containing emulsion.

Further, the weight ratio between the alcohol, the penetration enhancer and the diluent is (25-40): (30-50): (15-30), for example about 33:about 40:about 23.

Further, the alcohol-containing emulsion further comprises other auxiliary materials.

Further, the other auxiliary materials are selected from one or more of a thickener, a pH regulator, a bacteriostat and a stabilizer.

Further, the thickener is selected from one or more of carbomers, hydroxyethyl cellulose and hypromellose.

Further, the carbomer is carbomer homopolymer type a.

Further, the alcohol-containing emulsion comprises 0.1 wt% to 0.4 wt%, such as about 0.3 wt% thickener, based on the weight percent of the alcohol-containing emulsion.

Further, the pH adjuster is an alkaline substance such as triethanolamine.

Further, the alcohol-containing emulsion comprises 0.01 wt% to 1 wt%, further 0.01 wt% to 0.1 wt%, such as about 0.033 wt% of a pH adjuster, based on the weight percent of the alcohol-containing emulsion.

Further, in the alcohol-containing emulsion, about 50% or more of the emulsion particles have a particle size of not more than 10 μm and about 90% or more of the emulsion particles have a particle size of not more than 15 μm.

Further, in the alcohol-containing emulsion, about 50% or more of the emulsion particles have a particle size of not more than 5 μm and about 90% or more of the emulsion particles have a particle size of not more than 10. Mu.m.

According to another aspect of the present invention, there is provided a process for preparing the above alcohol-containing emulsion, comprising the steps of:

(1) Weighing appropriate amount of 5α -reductase inhibitor, alcohol, oil phase, emulsifier, diluent and penetration enhancer, heating and melting the oil phase and the emulsifier, adding 5α -reductase inhibitor, alcohol, diluent and penetration enhancer, emulsifying to obtain emulsion, and mixing

(2) The emulsion is cooled to obtain the alcohol-containing emulsion.

Further, the emulsification is homogeneous emulsification.

Further, the temperature of the emulsification is 70 ℃ to 90 ℃, for example 75 ℃ to 85 ℃.

Further, the water bath is a cold water bath, such as a low temperature water bath, such as an ice water bath.

Further, the 5α -reductase inhibitor is dutasteride and/or finasteride.

Further, the alcohol is ethanol, such as absolute ethanol.

Further, the wax is natural or synthetic wax.

Further, the cetostearyl alcohol polyether is cetostearyl alcohol polyether-20.

Further, the sucrose fatty acid ester is sucrose stearate.

Further, the sorbitol fatty acid ester is span 60.

Further, the behenpolyether is behenpolyether-5, behenpolyether-10, behenpolyether-20 and/or behenpolyether-30.

Further, the diluent is water, such as purified water.

Further, in the step (1), the method further comprises a step of weighing a proper amount of other auxiliary materials.

Further, in the step (2), the method further comprises the step of adding the other auxiliary materials and uniformly mixing.

Further, the carbomer is carbomer homopolymer type a.

Further, the pH adjuster is an alkaline substance, such as triethanolamine.

According to another aspect of the present invention there is provided the use of an alcohol-containing emulsion as described above in the manufacture of a medicament for the prevention and/or treatment of hair loss.

Further, the alcoholic emulsion further comprises one or more drugs and/or extracts for preventing and/or treating alopecia.

Further, the alopecia is androgenetic alopecia.

Further, the medicine is minoxidil, blood nourishing and hair growth promoting capsule, hair growth promoting pill and/or cystine tablet.

Further, the alcohol-containing emulsion is an external scalp emulsion.

The invention has the beneficial effects that:

The invention discloses an alcohol-containing emulsion of a 5 alpha-reductase inhibitor, which creatively uses the combination of a solid oil phase and fatty alcohol polyether, solves the technical problem that ethanol damages the stability of the emulsion, and prepares uniform and stable alcohol-containing emulsion. While the oil phase of existing emulsions typically contains a liquid component, it has been unexpectedly found herein that the oil phase and emulsifier, which are liquid at room temperature, can disrupt the stability of the alcohol-containing emulsion, and thus the oil phase and emulsifier of the present invention are semi-solid or solid at room temperature. Most of the commonly used emulsifying agents are dissolved by ethanol or interact with the ethanol, so that the emulsifying effect is poor, and the invention surprisingly finds that when the fatty alcohol polyether is compounded with other emulsifying agents, the optimized oil phase white beeswax/Vaseline can be well emulsified in a system with the alcohol-water ratio not exceeding 3:2, so as to form a stable emulsifying system. When the fatty chain contains 16-22 carbon atoms and the fatty alcohol polyether with the hydrophilic end containing 10-20 polyoxyethylene repeating units is compounded for use, the emulsification effect is optimal, and the obtained emulsion has round appearance and particle size not more than 15 mu m.

The oil phase ratio of the general oil-in-water emulsion is 10% -50%, the dosage and proportion of the prescription which is optimized according to the invention can be as low as 2.5% -6%, the product viscosity is far lower than that of the commercial emulsion and related patents, a stable emulsion system can be obtained under the condition of low oil phase and emulsifier dosage and low viscosity, and the product can be stored for a long time at room temperature without changing physicochemical properties. The alcohol-containing emulsion disclosed by the invention not only maintains the refreshing feel of the preparation with low solid content and alcohol content, is suitable for being used on scalp parts, but also avoids the defects of greasiness, hair adhesion and the like of the conventional emulsion, and fully exerts the advantages of improving the solubility of active ingredients, transdermal absorption and the like of the emulsion.

In addition, the present invention preferably provides suitable permeation enhancers propylene glycol and diethylene glycol monoethyl ether, which do not affect emulsion stability but also significantly improve transdermal absorption of the 5α -reductase inhibitor. The active ingredients can effectively penetrate through the stratum corneum barrier, the concentration of the medicine at the action part is far higher than that of the oral preparation, and the systemic exposure is far lower than that of the oral preparation, so that the curative effect and the safety of the medicine are improved.

Drawings

In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for the description of the embodiments will be briefly described below, and it will be apparent that the drawings in the following description are only some embodiments of the present invention, and that other drawings can be obtained according to these drawings by those skilled in the art without departing from the scope of the claimed invention.

FIG. 1 shows photomicrographs of inventive prescriptions 6, 7, and 8 (a) for 6,0 days, (b) for 7,0 days, (C) for 8,0 days, (d) for 6,5 ℃ for 15 days, (e) for 7,5 ℃ for 15 days, and (f) for 8,5 ℃ for 15 days.

Fig. 2 is a photomicrograph of an alcohol-containing emulsion (formulas 9-14) using different solid oil phases, respectively, (a) white petrolatum, (b) white beeswax, (c) stearyl alcohol, (d) behenyl alcohol, (e) cetyl palmitate, and (f) glyceryl behenate.

FIG. 3 is a photomicrograph of an alcohol-containing emulsion using different emulsifiers and combinations thereof (a) prescription 20, (b) prescription 21, (c) prescription 22, (d) prescription 23, (e) prescription 24, and (f) prescription 25.

FIG. 4 is a photomicrograph of alcohol-containing emulsions of varying solids content (a) prescription 26, (b) prescription 27, (c) prescription 29, and (d) prescription 30.

FIG. 5 is a photomicrograph of an alcohol-containing emulsion using a combination of different aliphatic alcohol polyethers (a) prescription 31, (b) prescription 32, (c) prescription 33, and (d) prescription 34.

FIG. 6 is a graph of the contour of the filtered residual predictive equation for alcohol-containing emulsions of varying proportions of white beeswax, cetostearyl alcohol polyether-20 and behenyl alcohol polyether 20 (a), a graph of the contour of the predictive equation for initial particle size D50 (C) for a3 day period at 40C, and a graph of the contour of the predictive equation for rate of change of particle size D50 (D) for a range of optimum proportions taken into consideration.

Fig. 7 is a photomicrograph of an alcohol-containing emulsion (recipe 56). Wherein, (a) an initial sample, (b) a sample after freeze thawing cycle, (c) a sample at low temperature for 6 months, and (d) a sample at high temperature for 6 months.

Fig. 8 is a graph of particle size and viscosity profile of an alcohol-containing emulsion (formulation 56) at elevated temperature.

Fig. 9 is a graph of particle size and viscosity profiles of an alcohol-containing emulsion (formulation 56) under low temperature and freeze-thaw cycle conditions.

Detailed Description

The following description of the embodiments of the present invention will be made clearly and fully with reference to the accompanying drawings, in which it is evident that the embodiments described are some, but not all embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

Unless otherwise defined, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains or to which this term applies. Although any methods, conditions, materials, or materials similar or equivalent to those disclosed herein can be used in the practice of the present invention, the preferred methods, conditions, materials, or materials are described herein.

The invention is intended to cover all alternatives, modifications and equivalents, which may be included within the art of the invention as defined by the appended claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that can be used in the practice of the present invention. The invention is in no way limited to the description of methods and materials.

As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

In the present invention, the term "comprising" is synonymous with "including". The terms "comprising," "including," "having," "containing," or any other variation thereof, as used herein, are intended to cover a non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, step, method, article, or apparatus.

The experimental methods for which specific conditions are not noted in the examples of the specification are generally according to the conventional conditions in the art or according to the conditions recommended by the manufacturer. In the present invention, "above", "below" and "within" mean that the present number is included unless otherwise specified.

As described in the background art section, the existing external preparation for treating alopecia has the problems of poor stability and poor emulsification. In order to solve the above problems, the present invention provides an alcohol-containing emulsion of a 5α -reductase inhibitor, which contains a 5α -reductase inhibitor, an alcohol, an oil phase, an emulsifier, a diluent, and a penetration enhancer.

In particular, the method comprises the steps of,

(1) The invention completes the following work:

1. through a saturated solubility experiment, liquid auxiliary materials such as ethanol, propylene glycol, diethylene glycol ethyl ether and the like with higher saturated solubility are screened out, and the concentration of dutasteride in the preparation can be greatly improved by the auxiliary materials.

2. Through liquid matrix composition screening experiments, the liquid matrix with the proportion of 33% ethanol-40% propylene glycol-23% purified water can be successfully emulsified.

3. White beeswax is selected as oil phase through single factor screening experiment to form milk smoothly.

4. Through an emulsion test, the specific oil phase type and the emulsifier and the proportion thereof which can successfully prepare the stable emulsion in an ethanol-propylene glycol-purified water prescription system are selected as follows:

a) The oil phase is white beeswax.

B) The emulsifier is behenate polyether-20 and cetostearyl alcohol ether-20.

5. The optimal proportion relation of white beeswax, cetostearyl alcohol ether-20 and behenyl alcohol polyether-20 is established by designing a prescription (DOE) according to the experimental variables A, B, C, namely white beeswax, cetostearyl alcohol ether-20 and behenyl alcohol polyether-20, and setting the variable range and constraint conditions to be 1.6< A < 2.2,0.5< B < 1.3,0.1< C < 0.6 and A+B+C=3. A total of 12 prescriptions were designed and examined for sample filtration residue, particle size distribution and particle size change after 40 ℃ placement. The filtration residue is used as a dependent variable, the three component dosages are used as independent variables, and the interval for forming milk by the three component dosages is found to be that the total amount of white beeswax and emulsifying agent (cetyl alcohol ether-20 and behenyl alcohol polyether-20) in the prescription is 2.5% -5%, the ratio of the white beeswax to the emulsifying agent is 2:1-1:2, and the ratio of the cetyl alcohol ether-20 to the behenyl alcohol polyether-20 in the emulsifying agent is 1:1-7:1.

6. The results of comparative pharmacokinetics experiments of the solution and a commercially available oral dutasteride preparation developed on a piglet model show that the emulsion of the invention generates a drug concentration which is 7 times higher than that of the oral dutasteride preparation in deep dermis (namely hair follicle part) after being applied to local skin, and the systemic exposure in blood is far lower than that of the oral preparation, thus the systemic exposure of the dutasteride alcohol-containing emulsion is far lower than that of the oral dutasteride soft capsule, and the toxic and side effects of dutasteride can be effectively reduced.

(2) The innovative content of the invention is as follows:

1. in order to obtain high enough drug concentration and transdermal quantity, an auxiliary material ethanol capable of solubilizing dutasteride and a liquid auxiliary material propylene glycol capable of maximally improving transdermal absorption quantity (the auxiliary material is also capable of increasing the solubility of dutasteride) are added into the preparation, and on the basis of combining the two auxiliary materials, the emulsification can be successfully carried out when water with a specific proportion (about 23%) is added. Finally, a liquid matrix with the proportion of 33% ethanol-40% propylene glycol-23% purified water is optimized, and the matrix can dissolve dutasteride medicine with high enough concentration (up to 0.2%), and can obtain remarkably higher transdermal drug quantity in a transdermal test simulating clinical use;

2. The greater the solvent-based auxiliary material ratio, the more difficult it is to emulsify, and the less likely it is to emulsify in the liquid matrix of the present invention having an organic solvent ratio of up to 73% (33% ethanol and 40% propylene glycol), but the present invention creatively finds that when an emulsifier having not less than 22 carbon (C22) saturated fatty chains is used, such as a less common emulsifier, behenpolyether, the emulsion can be successfully produced, and surprisingly also found that the number of oxyethylene repeating units of the polyether chain of the behenpolyether used must be between 5 and 25, a stable emulsion can be successfully produced in the liquid matrix, the emulsion particles of the resulting emulsion being very uniform and fine, with D50 as low as 5 μm and D90 as low as 10 μm.

3. It has also been unexpectedly found that in this "33% ethanol-40% propylene glycol-23% purified water" liquid matrix, in addition to the behenyl alcohol polyether, the additional co-use of a second "emulsifier having a saturated fatty chain length of 16-18 carbons", such as cetostearyl alcohol ether-20, also provides a more uniform, more stable emulsion of milk particles.

4. Through experimental design, a dosage range capable of successful emulsification is found, namely the total amount of white beeswax and emulsifier (cetostearyl alcohol ether-20 and behenyl alcohol polyether-20) in the prescription is 2.5% -5%, the ratio of the white beeswax to the emulsifier is 2:1-1:2, and the ratio of the cetostearyl alcohol ether-20 to the behenyl alcohol polyether-20 in the emulsifier is 1:1-7:1.

5. While the emulsion of the present invention achieves stable maintenance of the emulsion even at ultra-low viscosity because of the variety and amount of oil-emulsifier that can be emulsified sufficiently in the system unexpectedly obtained by experimental design in the system.

In summary, the invention is a "water-ethanol-polyol oil-in-water" emulsion based on "33% ethanol-40% propylene glycol-23% purified water", which is prepared by high shear emulsification using white beeswax (or other wax, oil, or hydrocarbon containing more than 18 carbon atoms per molecule) as the oil phase, and a mixture of cetostearyl ether-20 and behenyl alcohol polyether-20 as the emulsifier.

(3) The advantages of the invention over the prior art are as follows:

2. The dutasteride has extremely low solubility, and if the dutasteride is in a traditional solution form, the dutasteride is easy to precipitate and precipitate at low temperature, so that the concentration of the drug is reduced, and the concentration and the dosage accuracy of the drug are further affected. The prior art can dissolve enough dutasteride but cannot form milk, or can form milk but is not suitable for scalp application, while the prescription of the invention can dissolve enough dutasteride and can make enough drug absorbed transdermally, and can successfully emulsify to prepare fine emulsion, i.e. no drug crystal precipitate appears under refrigeration condition, thereby greatly improving the stability in storage and use.

3. In order to keep emulsion stable, the existing emulsion type external product needs to use a high percentage (usually more than 10 percent) of emulsifying agent, but the dosage of the emulsifying agent is as low as about 1.5 percent, and the less the stimulus of the emulsifying agent to the skin is, thus being very suitable for long-term daily administration of scalp.

4. The existing emulsion type scalp external cosmetics contain no more than 20% of ethanol, and because the ethanol is a demulsifier, the common emulsion can be demulsified and layered after encountering the ethanol, the emulsion has the ethanol content of 33% -34%, but the stability is far superior to that of the existing emulsion containing the ethanol, the emulsion can be kept stable after being stored at high temperature or low temperature for a long time, and the physicochemical property is not changed. Compared with the existing emulsion, the product with the high ethanol concentration has the advantages that (1) the transdermal absorption of the medicine can be improved by the ethanol with higher concentration, so that the bioavailability is improved, (2) the product can be volatilized and dried faster after being applied to the skin, the wet scalp and hair can be quickly restored to the normal state, the outgoing social contact is not influenced, and the medication compliance is improved, and (3) the prescription has the antiseptic capability without adding an antiseptic or adopting other antiseptic measures.

5. The total amount of non-volatile solid components in the preparation of the invention is very low and as low as about 3%, and the preparation has the advantages of little solid residue after use, light and thin skin feel, freshness and no sticky hair.

6. The preparation has low viscosity of 50-300 cp and is very suitable for scalp administration. The viscosity is higher than 50 cp, so that the hair can stay on the surface of the scalp without dripping during the administration, thereby avoiding the problem of inaccurate administration amount caused by dripping after the administration of the current commercial solution type liniment, meanwhile, when the common high-viscosity emulsifiable paste is used on scalp parts, the hair can be bonded into bundles or clusters, the hairstyle can not be kept, the user can not go out to social contact, the medication compliance of a patient is seriously influenced, and compared with the hair-care emulsifiable paste, the hair-care emulsifiable paste has lower viscosity (lower than 300 cp) and is light and thin, the hair can not be sticky and clustered during the administration, and the medication compliance of the patient is greatly improved.

7. The emulsion prepared according to the invention has very small and stable particle size, can stably maintain the D50 of the particle size distribution of the emulsion particles at high temperature (30 ℃) to be not more than 5 mu m, and has D90 of not more than 10 mu m. In contrast, existing emulsions either fail to emulsify into tiny emulsion particles in alcohol-containing systems, or the emulsion particles tend to agglomerate, or it is difficult to maintain stable particle size when stored at high or low temperatures. Surprisingly, the emulsion has very good stability and the particle size remains unchanged at both high and low temperatures.

8. At present, only one commercial dutasteride preparation (dutasteride soft capsule) is an oral preparation, and after oral administration, the systemic drug exposure is high and the side effect is large. After the emulsion is smeared on the skin of a piglet, the concentration of the drug generated in the target dermis layer (namely, the hair follicle layer) is 8 times higher than that of an oral preparation, the targeting capability of the target dermis layer is greatly improved, and the drug exposure (AUC) in the whole body blood circulation is only 1.2 percent of that of the oral preparation, so that the unnecessary whole body drug exposure is greatly reduced. Thus, the present invention has great clinical advantages over existing dutasteride formulations.

In the present invention, when parts by weight, time, pressure, proportions, equivalents, concentrations, or other values or parameters are expressed as ranges, preferred ranges, or ranges defined by a list of upper preferable values and lower preferable values, this should be understood to specifically disclose all ranges formed by any pairing of any upper range limit or preferred value with any lower range limit or preferred value, whether or not the ranges are separately disclosed. For example, when a range of "10% -35%" is disclosed, the described range should be interpreted as including the range "10%~35%"、"10%~30%"、"10%~25%"、"10%~20%"、"10%~15%"、"15%~35%"、"15%~30%"、"15%~25%"、"15%~20%"、"20%~35%"、"25%~30%"、"30%~35%", etc. When a numerical range is described herein, unless otherwise indicated, the range is intended to include its endpoints and all integers and fractions within the range.

In a preferred embodiment, the oil phase is not in a liquid form at ambient temperature.

In a preferred embodiment, the emulsifier is not in a liquid form at ambient temperature.

In a preferred embodiment, the emulsion does not comprise an oil phase that is liquid at ambient temperature.

In a preferred embodiment, the emulsion does not contain an emulsifier that is liquid at ambient temperature.

In a preferred embodiment, the 5α -reductase inhibitor comprises a hair tonic for external use on the scalp.

In a preferred embodiment, the 5α -reductase inhibitor is dutasteride and/or finasteride.

In a preferred embodiment, the alcohol-containing emulsion comprises 0.01 wt% to 0.5 wt% based on the weight percentage of the alcohol-containing emulsion.

In a preferred embodiment 0.02 wt% to 0.2 wt% of 5α -reductase inhibitor.

In a preferred embodiment, the alcohol is ethanol, such as absolute ethanol.

In a preferred embodiment, the alcohol-containing emulsion comprises 25 wt.% to 40 wt.%, e.g., about 33 wt.% alcohol, based on the weight percent of the alcohol-containing emulsion.

In the present invention, "about" means a value within + -5% of a specific value. For example, "about 33%" includes 33% plus or minus 5%, or from 31.35% to 34.65%.

In a preferred embodiment, the weight ratio between the alcohol and the diluent is not higher than (2.6-3.4): 1.6-2.4.

In a preferred embodiment, the oil phase is a hydrocarbon or wax that is not liquid at ambient temperature.

In a preferred embodiment, the hydrocarbonaceous material comprises saturated and/or unsaturated alkanes having more than 18 carbon atoms per molecule.

In a preferred embodiment, the wax comprises oils and/or solid waxes containing more than 18 carbon atoms per molecule.

In a preferred embodiment, the wax is a natural or synthetic wax.

In a preferred embodiment, the oil phase is selected from one or more of petrolatum, white beeswax and fatty alcohols containing more than 18 carbon atoms.

In a preferred embodiment, the fatty alcohol containing more than 18 carbon atoms is stearyl alcohol and/or behenyl alcohol.

In a preferred embodiment, the alcohol-containing emulsion comprises 1 wt.% to 2 wt.%, further 1.3 wt.% to 1.8 wt.%, such as about 1.72 wt.% of the oil phase, such as about 1.6 wt.% of the oil phase, such as about 1.489 wt.% of the oil phase, based on the weight percent of the alcohol-containing emulsion.

In the present invention, "about" means a value within + -5% of a specific value. For example, "about 1.72%" includes 1.72% plus or minus 5%, or from 1.634% to 1.806%, "about 1.6%" includes 1.6% plus or minus 5%, or from 1.52% to 1.68%, "about 1.489%," includes 1.489% plus or minus 5%, or from 1.41455% to 1.56345%.

In a preferred embodiment, the emulsifier is selected from one or more of the group consisting of fatty alcohol polyethers, sucrose fatty acid esters and sorbitol fatty acid esters.

In a preferred embodiment, the hydrophobic end of the fatty alcohol polyether contains at least 16 carbon atoms, for example 16 to 22 carbon atoms.

In a preferred embodiment, the hydrophilic end of the fatty alcohol polyether comprises 2 to 30 polyoxyethylene repeat units, for example 10 to 20 polyoxyethylene repeat units.

In a preferred embodiment, the fatty alcohol polyether is selected from one or more of the group consisting of a stearyl alcohol polyether, a cetyl alcohol polyether and a behenyl alcohol polyether.

In a preferred embodiment, the fatty alcohol polyether is selected from one or more of the group consisting of a stearyl alcohol polyether-2, a stearyl alcohol polyether-10, and a stearyl alcohol polyether-20.

In a preferred embodiment, the cetostearyl alcohol polyether is selected from one or more of cetostearyl alcohol polyether-5, cetostearyl alcohol polyether-10, cetostearyl alcohol polyether-15, cetostearyl alcohol polyether-20, cetostearyl alcohol polyether-25.

In a preferred embodiment, the cetostearyl alcohol polyether is cetostearyl alcohol polyether-20.

In a preferred embodiment, the sucrose fatty acid ester is sucrose stearate.

In a preferred embodiment, the sorbitol fatty acid ester is span 60.

In a preferred embodiment, the behenpolyether is selected from one or more of the group consisting of behenpolyether-5, behenpolyether-10, behenpolyether-20, and behenpolyether-30.

In a preferred embodiment, the behenpolyether is behenpolyether-30.

In a preferred embodiment, the behenpolyether is behenpolyether-20.

In a preferred embodiment, the alcohol-containing emulsion comprises a total of 2.5 to 6 wt.% of the oil phase and the emulsifier, for example a total of 2.7 to 5 wt.% of the oil phase and the emulsifier, based on the weight percent of the alcohol-containing emulsion.

In a preferred embodiment, the alcohol-containing emulsion comprises 0.5 wt% to 5wt%, further 1 wt% to 2.5 wt%, such as about 1.72 wt% oil phase, such as about 1.6 wt% oil phase, such as about 1.489 wt% oil phase, based on the weight percent of the alcohol-containing emulsion.

In a preferred embodiment, the alcohol-containing emulsion comprises from 1 wt% to 2 wt%, further from 1.3 wt% to 1.8 wt%, such as about 1.511 wt%, of an emulsifier, such as about 1.3 wt%, of an emulsifier, such as about 1.4 wt% of an emulsifier, based on the weight percent of the alcohol-containing emulsion.

In the present invention, "about" means a value within + -5% of a specific value. For example, "about 1.511%" includes ± 5% of 1.511%, or from 1.43545% to 1.58655%, "about 1.3%" includes ± 5% of 1.3%, or from 1.235% to 1.365%, "about 1.4%," includes ± 5% of 1.4%, or from 1.33% to 1.47%.

In a preferred embodiment, the weight ratio between the oil phase and the emulsifier is 1:2 to 5:1, further 1:2 to 2:1.

In a preferred embodiment, the weight ratio between the cetostearyl alcohol polyether-20 and the behenyl alcohol polyether-20 is 1:1 to 10:1, further 1:1 to 7:1.

In a preferred embodiment, the alcohol-containing emulsion comprises from 0.5 wt% to 2.0 wt%, further from 0.8 wt% to 1.4 wt%, such as about 1.254 wt% of cetostearyl alcohol-20, such as about 1.117 wt% of cetostearyl alcohol-20, such as about 1.03 wt% of cetostearyl alcohol-20, based on the weight percent of the alcohol-containing emulsion.

In the present invention, "about" means a value within + -5% of a specific value. For example, "about 1.254%" includes 1.254% plus or minus 5%, or from 1.1913% to 1.3167%, "about 1.17%" includes 1.17% plus or minus 5%, or from 1.1115% to 1.2285%, "about 1.03%," includes 1.03% plus or minus 5%, or from 0.9785% to 1.0815%.

In a preferred embodiment, the alcohol-containing emulsion comprises 0.1 wt.% to 0.8 wt.%, further 0.2 wt.% to 0.6 wt.%, for example about 0.257 wt.% behenyl polyether-20, for example about 0.283 wt.% behenyl polyether-20, for example about 0.414 wt.% behenyl polyether-20, based on the weight percent of the alcohol-containing emulsion.

In the present invention, "about" means a value within + -5% of a specific value. For example, "about 0.257%" includes 0.257% of + -5%, or from 0.24415% to 0.26985%, "about 0.283%" includes 0.283% of + -5%, or from 0.26885% to 0.29715%, "about 0.414%," includes 0.414% of + -5%, or from 0.3933% to 0.4347%.

In a preferred embodiment, the diluent is water, such as purified water.

In a preferred embodiment, the alcohol-containing emulsion comprises 15 wt% to 30 wt%, such as about 23 wt% water, based on the weight percent of the alcohol-containing emulsion.

In the present invention, "about" means a value within + -5% of a specific value. For example, "about 23%" includes ±5% of 23%, or from 21.85% to 24.15%.

In a preferred embodiment, the permeation enhancer is diethylene glycol monoethyl ether and/or propylene glycol.

In a preferred embodiment, the alcohol-containing emulsion comprises 10 wt% to 50 wt%, further 30 wt% to 50 wt%, such as about 40 wt% penetration enhancer, based on the weight percent of the alcohol-containing emulsion.

In the present invention, "about" means a value within + -5% of a specific value. For example, "about 40%" includes 40% plus or minus 5%, or from 38% to 42%.

In a preferred embodiment, the weight ratio between the alcohol, the penetration enhancer and the diluent is (25-40): (30-50): (15-30), for example about 33:about 40:about 23.

In the present invention, "about" means a value within + -5% of a specific value. For example, "about 33" includes 33.+ -. 5%, or from 31.35 to 34.65%, and "about 40" includes 40.+ -. 5%, or from 38 to 42%, and "about 23" includes 23.+ -. 5%, or from 21.85 to 24.15.

In a preferred embodiment, the alcohol-containing emulsion further comprises other adjuvants.

In a preferred embodiment, the additional adjuvant is selected from one or more of a thickener, a pH adjustor, a bacteriostat, and a stabilizer.

In a preferred embodiment, the thickener is selected from one or more of carbomers, hydroxyethylcellulose and hypromellose.

In a preferred embodiment, the carbomer is carbomer homopolymer type a.

In a preferred embodiment, the alcohol-containing emulsion comprises 0.1 wt% to 0.4 wt%, such as about 0.3 wt% thickener, based on the weight percent of the alcohol-containing emulsion.

In the present invention, "about" means a value within + -5% of a specific value. For example, "about 0.3%" includes 0.3% plus or minus 5%, or from 0.285% to 0.315%.

In a preferred embodiment, the pH adjuster is an alkaline substance, such as triethanolamine.

In a preferred embodiment, the alcohol-containing emulsion comprises 0.01 wt% to 1wt%, further 0.01 wt% to 0.1wt%, such as about 0.033 wt% of a pH adjuster, based on the weight percent of the alcohol-containing emulsion.

In the present invention, "about" means a value within + -5% of a specific value. For example, "about 0.033%" includes 0.033% plus or minus 5%, or from 0.03135% to 0.03465%.

In a preferred embodiment, in the alcohol-containing emulsion, about 50% or more of the emulsion particles have a particle size of not more than 10 μm and about 90% or more of the emulsion particles have a particle size of not more than 15 μm.

In a preferred embodiment, in the alcohol-containing emulsion, about 50% or more of the emulsion particles have a particle size of no more than 5 μm and about 90% or more of the emulsion particles have a particle size of no more than 10 μm.

In the present invention, "about" means a value within + -5% of a specific value. For example, "about 50%" includes 50% plus or minus 5%, or from 47.5% to 52.5%, "about 90%" includes 90% plus or minus 5%, or from 85.5% to 94.5%.

(2) The emulsion is cooled to obtain the alcohol-containing emulsion.

In a preferred embodiment, the emulsification is a homogeneous emulsification.

In a preferred embodiment, the temperature of the emulsification is 70 ℃ to 90 ℃, for example 75 ℃ to 85 ℃.

In a preferred embodiment, the water bath is a cold water bath, such as a low temperature water bath, such as an ice water bath.

In a preferred embodiment, the alcohol-containing emulsion comprises 0.01 wt% to 0.5 wt%,

In a preferred embodiment 0.02 wt% to 0.2 wt% of 5α -reductase inhibitor.

In a preferred embodiment, the alcohol is ethanol, such as absolute ethanol.

In a preferred embodiment, the wax is a natural or synthetic wax.

In a preferred embodiment, the alcohol-containing emulsion comprises 1 wt.% to 2 wt.%, further 1.3 wt.% to 1.8 wt.%, further 1.4 wt.% to 1.8 wt.%, such as about 1.72 wt.% of the oil phase, such as about 1.6 wt.% of the oil phase, such as about 1.489 wt.% of the oil phase, based on the weight percent of the alcohol-containing emulsion.

In a preferred embodiment, the sucrose fatty acid ester is sucrose stearate.

In a preferred embodiment, the sorbitol fatty acid ester is span 60.

In a preferred embodiment, the behenpolyether is behenpolyether-5, behenpolyether-10, behenpolyether-20 and/or behenpolyether-30.

In a preferred embodiment, the alcohol-containing emulsion comprises a total of 2.5 to 6 wt.% of the oil phase and the emulsifier, for example a total of 3 to 5 wt.% of the oil phase and the emulsifier, based on the weight percent of the alcohol-containing emulsion.

In the present invention, "about" means a value within + -5% of a specific value. For example, "about 1.72%" includes 1.72% plus or minus 5%, or from 1.634% to 1.806%, "about 1.6%" includes 1.6% plus or minus 5%, or from 1.52% to 1.68%, "about 1.634%" includes 1.634% plus or minus 5%, or from 1.5523% to 1.7157%.

In the present invention, "about" means a value within + -5% of a specific value. For example, "about 1.254%" includes 1.254% plus or minus 5%, or from 1.1913% to 1.3167%, "about 1.117%" includes 1.117% plus or minus 5%, or from 1.06115% to 1.17285%, "about 1.03%," includes 1.03% plus or minus 5%, or from 0.9785% to 1.0815%.

In a preferred embodiment, the diluent is water, such as purified water.

In a preferred embodiment, in step (1), the method further comprises the step of weighing an appropriate amount of other auxiliary materials.

In a preferred embodiment, in step (2), the method further comprises the step of adding the other auxiliary materials and uniformly mixing.

In a preferred embodiment, the carbomer is carbomer homopolymer type a.

In a preferred embodiment, the alcohol-containing emulsion further comprises one or more drugs and/or extracts for preventing and/or treating hair loss.

In a preferred embodiment, the hair loss is androgenetic hair loss.

In a preferred embodiment, the medicament is minoxidil, a blood-nourishing hair-growing capsule, a hair-growing pill and/or a cystine tablet.

In a preferred embodiment, the alcohol-containing emulsion is a scalp external emulsion.

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples, in which specific conditions are not noted, are generally according to conventional conditions or conditions suggested by manufacturers.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.

The above-mentioned features of the invention, or of the embodiments, may be combined in any desired manner. All of the features disclosed in this patent specification may be combined with any combination of the features disclosed in this specification, and the various features disclosed in this specification may be substituted for any alternative feature serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the disclosed features are merely general examples of equivalent or similar features.

Examples

In the invention, the materials and reagents used are all commercial products, are conventional reagents and can be obtained by a commercial method.

Preparation of alcohol-containing emulsions

The following examples were prepared as follows, unless otherwise indicated:

The preparation of the oil phase comprises the steps of weighing the oil phase and the emulsifier, heating, melting and uniformly mixing, and preserving heat at 75-85 ℃ for later use;

preparing water phase by adding anhydrous ethanol (if active ingredient is dissolved in the anhydrous ethanol), purified water, and penetration enhancer into a container, mixing, and heating to 75-85deg.C;

mixing the water phase and the oil phase, homogenizing under 6000-15000 rpm with stator-rotor type emulsifying homogenizer;

Cooling, standing the sample in cold water bath after homogenization, cooling, and

5. Adding thickener, and mixing.

Example 1 selection of permeation enhancers

As a poorly soluble drug, dutasteride should have as high a solubility as possible in an external preparation to ensure that a sufficient amount of the drug is in a molecular state and absorbed by the cortex. As can be seen from table 1, dutasteride was not transdermally absorbed in ethanol-water solution (60:40), and transdermally absorbed significantly increased upon addition of a permeation enhancer. The solubility of dutasteride in different penetration enhancers is greatly different, and only the penetration enhancer auxiliary materials which can be dissolved well enough to measure dutasteride and are mutually soluble with water can play a role in the emulsifying system of the invention.

TABLE 1 selection of permeation enhancers

Ethanol and water are used as water phases, different permeation promoters are used for preparing emulsion, and the permeation promoters are screened. It was found that most penetration enhancers affect the stability of the alcohol-containing emulsion. For example, propylene glycol monocaprylate, propylene glycol monolaurate, caprylic acid capric acid monodiglycerol, 15-hydroxystearic acid polyethylene glycol ester and the like can be dissolved or partially dissolved in ethanol, so that oil-water phase separation is caused, and milk formation is not possible, and polyethylene glycol 400, isopropyl palmitate and menthol can interact with oil phase or emulsifying agent to influence the emulsification effect, so that milk particles are agglomerated or precipitated. It has been unexpectedly found that diethylene glycol monoethyl ether and propylene glycol are miscible with ethanol and water without affecting the stability of the emulsion system, and that the resulting emulsion is stable and phase-separated.

Alcohol-containing emulsions containing diethylene glycol monoethyl ether or propylene glycol (partially formulated with menthol or caprylic capric acid mono-diglycerides) were prepared according to the formulations shown in table 2 and examined for the centrifugal stability of the emulsion and for the transdermal absorption of the drug In Vitro (IVPT). The results show that the above prescription samples were centrifuged at 12000 rpm for 10 minutes, neither of the prescription containing diethylene glycol monoethyl ether nor propylene glycol had delaminated after centrifugation, whereas the stability of the emulsion of the prescription containing menthol or caprylic acid mono-diglyceride was reduced and delamination occurred after centrifugation. The transdermal absorption of the drug prescribed above was studied using a vertical diffusion cell and an ex vivo pig skin, the receiving medium was 0.5% Tween80 solution, the horny layer was removed with tape after 48 hours of administration, and the cumulative transdermal amount (μg/g) of drug in the epidermis and dermis was measured. The results show that after diethylene glycol monoethyl ether or propylene glycol is added to the prescription, the medicine can penetrate through the stratum corneum to reach the action site. Compared with the traditional solution shown in Table 1, the transdermal absorption of the alcohol-containing emulsion is better, and the medicines distributed in epidermis and dermis can form a reservoir to realize the long-acting slow release effect. Propylene glycol has better penetration promoting effect than diethylene glycol monoethyl ether, and when the dosage of propylene glycol is increased from 20% to 50%, the cumulative penetration amount of the medicine in epidermis and dermis is increased from 7.5 mug/g to 8.7 mug/g, and the transdermal absorption of the medicine is increased along with the increase of the dosage of the penetration promoting agent. After menthol or caprylic-capric acid mono-diglyceride are added in the prescription, the transdermal absorption of the medicine is not obviously increased compared with the transdermal absorption of the medicine by propylene glycol or diethylene glycol monoethyl ether.

TABLE 2 screening of permeation enhancers

In summary, the permeation enhancer in the present invention is selected from diethylene glycol monoethyl ether or propylene glycol, preferably propylene glycol. The dosage of the penetration enhancer is 10% -50%, preferably 30% -50%.

Example 2 selection of oil phase

Alcohol-containing emulsions containing different oil phases were prepared according to the formula shown in Table 3, the emulsifier being behenyl alcohol polyether-5, the oil phase being behenyl alcohol and squalene (formula 6)/light liquid paraffin (formula 7)/white beeswax (formula 8). The study shows that 3 prescriptions are uniform and fine viscous emulsion and are microscopic to be uniformly distributed fine emulsion particles (fig. 1a, 1b and 1C), but after the sample is placed for 15 days at 5 ℃, the appearances of the prescriptions 6 and 7 are pearlescent, so that crystals are separated out from the sample, clustered crystals are microscopic to be observed (fig. 1d and 1 e), and the appearance and the microscopic structure of the prescriptions 8 are not significantly changed (fig. 1 f). The results show that when the formula contains liquid oil, the oil phase is separated out and phase separation occurs in the storage process of the emulsion, and when the oil phase is solid, the stability of the emulsion is obviously improved. Thus, the alcohol-containing emulsion of the present invention should be free of an oil phase that is liquid at room temperature.

TABLE 3 comparison of solid oil phase to liquid oil phase

Alcohol-containing emulsions were prepared as shown in Table 4 with propylene glycol, ethanol and water as aqueous phases, steareth-2 and cetostearyl alcohol polyether-20 as emulsifiers, and further examined for the emulsification effect of the different oil phases. As shown in fig. 2, when the oil phase is white vaseline (fig. 2 a) and white beeswax (fig. 2 b), the oil phase can be emulsified into uniformly distributed fine emulsion particles, when the oil phase is stearyl alcohol (fig. 2 c) and behenyl alcohol (fig. 2 d), although white viscous emulsion is obtained, the oil phase and the emulsifier can form liquid crystal (sheet or fiber-shaped structure in the figure), so that the sample precipitates, the liquid crystal structure is sensitive to ambient temperature, shearing force and the like, the liquid crystal structure can be changed during long-term storage, the emulsion stability is affected, and when the oil phase is hexadecyl palmitate (fig. 2 e) and glyceryl behenate (fig. 2 f), the oil phase emulsification effect is poor, the oil-water phase is separated, and a large amount of unemulsified oil phase clusters can be seen under a microscope.

In summary, the alcohol-containing emulsion of the present invention should not contain an oil phase that is liquid at room temperature. In particular, white vaseline or white beeswax shows a significantly better appearance in aqueous phase matrix (composed of ethanol, water, propylene glycol) than other solid oil phases, and the obtained emulsion particles have smaller particle size and more uniform distribution.

TABLE 4 screening of solid oil phases

Example 3 selection of emulsifier classes

Alcohol-containing emulsions containing different emulsifiers and combinations of emulsifiers were prepared according to the formulations shown in tables 5 and 6, and the appearance and microscopic properties of the products were examined, preferably the combination with the best emulsification effect.

The emulsification effect evaluation criteria were as follows:

the emulsion has the advantages of uniform appearance, no particle precipitation, uniform distribution of emulsion particles and small particle size

Preferably, the emulsion forms a white emulsion with uniform appearance, no or little particle deposition, and the emulsion particles are observed to have irregular shape or agglomeration in a microscopic way

Intermediate, white emulsion can be formed, but more particles are precipitated, and microscopic observation shows that part of the oil phase is not emulsified

Poor oil-water phase delamination or visual massive precipitation

TABLE 5 formulation and emulsion Effect of emulsions Using different emulsifiers

TABLE 6 emulsion formulation and emulsion Effect Using Complex emulsifiers

The effect of different emulsifiers on emulsifying white beeswax in an ethanol-water-propylene glycol matrix (Table 5) was examined, and the fatty alcohol polyether type emulsifier was found to have the best emulsifying effect, the emulsion particles were uniformly distributed and the particle size was small, the emulsion effect of span 60 and sucrose stearate was inferior, although white beeswax could be emulsified, the emulsion particles were observed to agglomerate under microscopic observation, the precipitation occurred at the bottom of the sample, polyethylene glycol 7 stearate and polyoxyethylene fatty acid ester could not well emulsify white beeswax, the sample oil-water phase was separated, and a large amount of unemulsified oil phase clusters were observed under microscopic observation.

Unexpectedly, the fatty alcohol polyether emulsifier can be compounded with any other emulsifier to obviously improve the emulsifying effect. As shown in tables 5, 6 and 3, the preparation using sucrose stearate (formula 20 in FIG. 3 a) or cetostearyl alcohol polyether-20 (formula 21 in FIG. 3 b) as the emulsifier is easy to agglomerate, and when the two are compounded for use (formula 22 in FIG. 3 c), the emulsifying effect is obviously improved, the emulsion is observed to have no agglomeration, almost no solid particles remain on the filter screen after passing through the 80-mesh filter screen, and no non-emulsified oil phase or agglomerated and precipitated emulsion particles exist in the product. Similarly, prescription 24 uses behenpolyether-5 as emulsifier, which can obtain even and fine white emulsion without particle precipitation, but microscopic observation can see fibrous liquid crystal structure (figure 3 e) which can affect long-term stability of the sample, while prescription 25 has the same amount of other components as prescription 24, only the emulsifier is changed into the combination of behenpolyether-5 and span 60, the emulsion particles are round, the liquid crystal structure is basically disappeared, and the microscopic appearance of the emulsion is obviously improved (figure 3 f). After the prescription 25 is stored for 1 month at 40 ℃, the appearance and microscopic properties are not changed, and the sample stability is good.

It has also been found that the best emulsifying effect can be achieved by compounding two emulsifiers which are both fatty alcohol polyethers. Formulation 22 and formulation 23 were compounded with sucrose stearate and behenate-10, respectively, with cetostearyl ether-20, and microscopic observation indicated that the emulsion morphology of formulation 23 (fig. 3 d) was more rounded, no emulsion aggregation was observed, and the emulsion particle size was significantly lower than that of formulation 22 (fig. 3 c). The two samples were placed in Lumisizer dispersion analyzer and centrifuged at 25 ℃ for 6 hours at 4000 rpm (simulating room temperature storage stability for 2 years), after centrifugation of formula 22 the emulsion particles settled, but after centrifugation of formula 23 the emulsion particles remained well dispersed in the aqueous matrix with little settling, demonstrating that the stability of the emulsion of formula 23 compounded with two fatty alcohol polyethers was significantly better than that of formula 22 using fatty alcohol polyether and sucrose stearate.

In summary, the emulsifier of the alcohol-containing emulsion of the present invention is formulated using two or more emulsifiers. One of the emulsifiers is preferably a fatty alcohol polyether and the other emulsifier is selected from the group consisting of sorbitol fatty acid esters, sucrose stearates, or fatty alcohol polyethers, more preferably the emulsifier is a combination of fatty alcohol polyethers.

Example 4 oil phase and emulsifier usage

Alcohol-containing emulsions were prepared by using propylene glycol, ethanol and water as aqueous phases and using steareth-2 and cetostearyl alcohol-20 as emulsifiers, respectively, according to the formulations shown in Table 7, and the influence of the total amount of the oil phase and the surfactant (hereinafter referred to as solid content) on the physicochemical properties of the formulations was examined. It was found that the ratio of oil phase to emulsifier was 3:1 for both formulation 26 (FIG. 4 a) and formulation 27 (FIG. 4 b), 4:1 for steareth-2 to cetostearyl alcohol polyether-20, and 2% and 2.67% solids, respectively, with similar particle size distribution and microtopography for both formulations. However, centrifugation of the sample at 25℃for 6 hours (simulating 2 years stability at room temperature) at 4000 rpm resulted in delamination after centrifugation of the 2% solids formulation 26, whereas no delamination was observed in formulation 27, indicating that the emulsion remained stable and that at lower solids the emulsion was prone to sedimentation, requiring the addition of a thickener to stabilize the emulsion. Recipe 28 and recipe 27 had the same surfactant composition ratio, similar oil phase to surfactant ratio, and increased solids content from 2.67% to 5%, with no significant differences in centrifuge stability, particle size distribution, and microscopic morphology. The emulsion effect was good when the solids content of recipe 29 (fig. 4 c) increased to 6%, but the emulsion particle size increased significantly, and the emulsion particle size was large and the emulsion was incomplete when the solids content of recipe 30 (fig. 4 d) increased to 6.67%, and the oil phase precipitated to form a precipitate.

The above studies show that the suitable total amount of oil phase and emulsifier in the alcohol-containing emulsion of the present invention is 2.5% -6%, more preferably 3% -5%.

TABLE 7 formulations of different oil phases and emulsifier usage

Example 5 chain length of fatty chain and polyoxyethylene chain of emulsifier

Earlier studies found that the fatty chain portion (hydrophobic end) of the fatty alcohol polyether should contain at least 16 carbon atoms so that the emulsifier is uniformly distributed on the surface of the emulsion particles, avoiding extraction of the emulsifier into the aqueous phase by ethanol, and thus deteriorating the stability of the emulsion. Thus, the aliphatic alcohol polyether having 16 to 22 carbon atoms in the aliphatic chain was selected for compounding, and an emulsion was prepared according to the prescription shown in Table 8, and examined for appearance, microscopic character, emulsification effect and particle size distribution.

To examine the emulsification effect, a certain amount of emulsion was filtered with a 500 mesh screen, and then the screen was dried in a 50 ℃ oven, weighed, and the ratio of the residue on the screen (the non-emulsified oil phase or agglomerated precipitated emulsion particles) to the oil phase and the emulsifier charge was calculated and reported as% filtration residue as shown in table 8. Further, the microscopic morphology and particle size distribution of the emulsion were examined with a polarizing microscope and a laser particle sizer, respectively, and the examination results are shown in fig. 5 and table 8, respectively.

Table 8 emulsion formulations and examination results for different fatty alcohol polyether combinations

The research shows that the cetostearyl alcohol ether-20 and other fatty alcohol polyethers have the best emulsification effect. For example, prescription 32 used a combination of cetostearyl ether-20 and behenyl alcohol polyether-10, the resulting emulsion was fine and uniform, microscopic observation was free of agglomeration (FIG. 5 b), and the emulsion particle size was less than 10 μm. While prescription 31 replaced cetostearyl ether-20 with cetostearyl ether-25, although a fine and uniform appearance of the emulsion was obtained, microscopic observation showed that the emulsion particles were partially agglomerated (FIG. 5 a), the filtration residue was increased from 0.55% to 1.63%, and the particle size was also increased from 8.74 μm to 11.9. Mu.m.

The chain length of polyoxyethylene chain (hydrophilic end) of fatty alcohol polyether was examined, and the result showed that when the chain length of polyoxyethylene was 2 to 5, the emulsion easily formed liquid crystals, thereby affecting the stability and use feeling of the product. For example, formulations 10, 27 used steareth-2 and formulations 16, 24, 25 used beheneth-5, all of which showed fibrous liquid crystal structure under microscopic observation, could affect emulsion stability. The formula 32-35 uses the emulsifier with polyoxyethylene chain length of 10-30, the microscopic observation does not see the liquid crystal structure, the emulsion particles are round, and the particle size of the emulsion particles is smaller than 15 mu m, more preferably, when the polyoxyethylene chain length is 10-20, the particle size of the emulsion particles is smaller than 10 mu m. Microscopic examination, on the other hand, showed that formulation 32 containing behenpolyether-10 still had a slight liquid crystalline structure (fig. 5 c), whereas formulation 34 using behenpolyether-20 was a uniform distribution of fine emulsion particles (fig. 5 d), and that the filtration residue of formulations 34, 35 was lower than formulations 32, 33 containing behenpolyether-10. When the chain length of the polyoxyethylene chain is increased, the hydrophilicity of the fatty alcohol polyether is increased, and the emulsification effect is better, but when the chain length of the polyoxyethylene chain is further increased, the fatty alcohol polyether is partially dissolved in ethanol, and the emulsion stability is damaged.

In summary, the alcohol-containing emulsion of the present invention uses a fatty alcohol polyether emulsifier whose hydrophobic end should contain at least 16 carbon atoms, more preferably, whose hydrophobic end should contain 16 to 22 carbon atoms, and whose hydrophilic end should contain 2 to 30 polyoxyethylene repeating units, more preferably, whose hydrophilic end should contain 10 to 20 polyoxyethylene repeating units.

EXAMPLE 6 composition ratio of oil phase and emulsifier

Propylene glycol, ethanol and water are used as water phases, white beeswax is used as an oil phase, cetostearyl alcohol polyether-20 and behenyl alcohol polyether-20 are used as emulsifying agents, the total consumption of the oil phase and the emulsifying agents is set to be 3%, dutasteride emulsion with 0.2% specification is prepared according to the formula shown in table 9, and microscopic properties, emulsification effects (filtering residues) and particle size distribution of samples are inspected to determine the optimal proportion of the oil phase and the emulsifying agents.

Table 9 emulsion formulations and investigation results containing different proportions of oil phase and emulsifier

As shown in Table 9, the white beeswax of the formulation 37-41 was used in an amount of 1% -2.5%, i.e., the ratio of oil phase to emulsifier was 1:2-5:1, the resulting emulsion was uniform and fine, almost no particle precipitation, particle size was less than 10 μm, and the particle size did not change significantly after 3 days of standing at 40 ℃. The white beeswax of prescription 36 was less than 1%, although the initial particle size was less than 10 μm, the emulsion particles agglomerated and flocculated after 3 days at 40 ℃ and the particle size increased to 191 μm. The filtration residue of prescription 39, which is 2.5% of the white beeswax, is significantly higher than that of prescriptions 38, 39, and a small amount of white beeswax crystals which are not completely emulsified are microscopically visible, indicating that the emulsification effect is reduced when the white beeswax is more than 2%. Therefore, the amount of white beeswax is preferably 1% -2%.

The amounts of white beeswax used in formulations 40, 38 and 41 were similar, and the ratios of cetostearyl alcohol polyether-20 and behenyl alcohol polyether-20 were from small to about 1:7, 1:1 and 10:1, respectively, to give homogeneous emulsions with almost no particle precipitation and particle size less than 10 μm, with no significant change in particle size after 3 days at 40 ℃. However, the ratio of the cetostearyl alcohol polyether-20 to the behenyl alcohol polyether-20 in the prescription 40 is less than 1:1, the filtering residues are obviously higher than those in the prescriptions 38 and 41, and the emulsifying effect is better when the cetostearyl alcohol polyether-20 in the prescription is higher than the behenyl alcohol polyether-20. Thus, the ratio of cetostearyl alcohol polyether-20 to behenyl alcohol polyether 20 is preferably from 1:1 to 10:1.

The optimum ratio of white beeswax, cetostearyl alcohol polyether-20 and behenyl alcohol polyether 20 was established according to the above study by designing the prescription (DOE) by setting the experimental variables A, B, C to white beeswax, cetostearyl alcohol polyether-20 and behenyl alcohol polyether-20, respectively, with variable ranges and constraints of 1.6< A.ltoreq.2, 0.5< B.ltoreq.1.3, 0.1< C.ltoreq.0.6, A+B+C=3. A total of 12 prescriptions were designed and examined for sample filtration residue, particle size distribution and particle size change after 40 ℃ placement. The composition ratios and investigation results of the prescriptions are shown in Table 10 and FIG. 6.

Table 10 emulsion formulations of different white beeswax, cetostearyl alcohol polyether-20 and behenyl alcohol polyether-20 ratios and examination results

The data from table 10 were fitted with the filtration residue as a dependent variable and the amounts of the three components as independent variables (fig. 6 a), and the prediction shows that the filtration residue is linear with the amount of white beeswax in the formulation, the lower the amount of white beeswax, the less filtration residue, indicating less emulsion particles in the non-emulsified oil phase or agglomerated precipitate. Fitting was performed with the initial particle size D50 as a function and the amounts of the three components as independent variables (FIG. 6 b), which shows that the lower the amount of white beeswax, the higher the ratio of cetostearyl alcohol polyether-20 in the emulsifier, and the smaller the initial particle size. When the white beeswax is used in an amount of less than 1.8% and the ratio of cetostearyl alcohol polyether-20 to behenyl alcohol polyether-20 is higher than 2:1, the initial particle size D50 is less than 3.5. Mu.m. The rate of change of D50 after 3 days of standing at 40℃was fitted as a dependent variable (FIG. 6C), and the results showed that the change in particle size was mainly related to the amount of the behenpolyether 20, the higher the behenpolyether-20 was, the smaller the change in particle size was, and when the amount of the behenpolyether 20 was more than 0.2%, the change in particle size after standing at high temperature was not more than 5%, indicating that the emulsion stability was better. That is, more preferably, the ratio of cetostearyl alcohol polyether-20 to behenyl alcohol polyether 20 in the formulation should be no greater than 6:1. Considering the above factors together (fig. 6 d), the optimal composition of the oil phase and the emulsifier in the formulation is 1.4% -1.8% white beeswax, 0.8% -1.4% cetostearyl alcohol polyether-20 and 0.2% -0.6% behenyl alcohol polyether-20.

Thus, the ratio of white beeswax to emulsifier in the formulation is preferably 2:1-1:2, and the ratio of cetostearyl alcohol polyether-20 to behenyl alcohol polyether-20 is preferably 1:1-7:1.

Example 7 alcohol-containing emulsions of different ethanol usage and different Specifications

The solubility of dutasteride in ethanol is better, the larger the ethanol ratio in the prescription is, the better the solubility of dutasteride is, and meanwhile, the preparation can be volatilized quickly, so that the skin feel is fresh. However, high proportions of ethanol may damage the stability of the emulsion, resulting in demulsification. Earlier studies showed that ethanol had less effect on emulsion stability when the ratio of ethanol to water in the formulation was no higher than 3:2. The solubility of dutasteride in the mixed solvent of propylene glycol, ethanol and water in different proportions is shown in table 11, and the prescription of dutasteride emulsion with 0.02% specification should at least contain 20% ethanol, and if the specification is increased to 0.2%, the prescription should at least contain 30% ethanol. The increase in propylene glycol dosage promotes dissolution and transdermal absorption of the drug, but higher propylene glycol dosage also increases skin irritation, as shown in example 1, with an optimal propylene glycol dosage of 30% -50%. The optimal weight ratio of ethanol, water and propylene glycol in the matrix of the present invention is about 33:about 23:about 40, taking into account the combination of formulation stability, solubility of dutasteride and transdermal absorption.

Table 11 solubility of tasmale amine in propylene glycol, ethanol and Water Mixed solvents

Dutasteride emulsions of 0.2% and 0.05% gauge were prepared according to the prescription of table 12 with ethanol at 34% and 25% respectively. As a result of examination, the emulsion of alcohol containing different amounts of ethanol has good emulsifying effect, less filtration residue and emulsion particle size smaller than 10 μm. The lower the amount of ethanol used, the smaller the particle size of the emulsion obtained. The two samples were left at 40 ℃ for 3 days without significant changes in particle size and microscopic properties. In addition, when the sample is placed at the temperature of 2-8 ℃, the microscopic properties are kept unchanged, needle-shaped dutasteride crystals are not seen, so that dutasteride can be well dissolved in emulsion, and precipitation cannot occur even when the sample is placed at a low temperature.

Table 12 dutasteride emulsions of 0.2% and 0.05% gauge

Example 8 formulation containing thickener and stability thereof

Alcohol-containing dutasteride solutions with different thickener dosages were prepared according to the prescription of table 13, and when the carbomer dosage was 0.2%, 0.3% and 0.4%, the viscosity of the formulations was 92.2cP, 166.8cP and 260.4cP, respectively, and the emulsion flowability was good, and when the carbomer dosage was higher than 0.5%, the viscosity of the formulations was higher and the flowability was poor. Taking prescription 56 as an example, the stability of an alcohol-containing emulsion under conditions of high temperature (30 ℃), low temperature (2 ℃ C. To 8 ℃) and freeze-thaw cycles (about 48 hours at-20 ℃ C. And 25 ℃ C., three cycles), respectively, was examined. As can be seen from fig. 7, the samples undergo freeze thawing cycle or have no obvious change in microscopic morphology after being left under the conditions of high temperature and low temperature for 6 months, the emulsion particles are round and have no agglomeration, and at the same time, no acicular dutasteride crystals are precipitated by microscopic observation, so that dutasteride can be well dissolved in the emulsion, and no precipitation occurs under each condition. As can be seen from fig. 8 and 9, the particle size and viscosity were not significantly changed after the sample underwent freeze-thawing cycle or was left under high and low temperature conditions for 6 months.

In conclusion, the usage amount of the thickener is 0.1% -0.4%, the viscosity of the emulsion is far lower than that of other alcohol-containing emulsions and related patents, good fluidity can be maintained, and the emulsion is suitable for scalp application. Meanwhile, the physical and chemical properties of the alcohol-containing emulsion are not obviously changed under the conditions of high temperature, low temperature and freeze thawing, and the stability is obviously better than that of the prior art.

Table 13 results of alcohol-containing emulsion formulations, viscosity and particle size investigation using different thickeners

EXAMPLE 9 transdermal absorption of alcohol-containing emulsions

The pharmacokinetics of 0.02%, 0.06% and 0.2% specification alcohol-containing tamarind emulsions were studied following dermal administration using 1-3 month old Bama piglets as models. The test group was given 0.5 mL daily on the skin of the back of the piglets, for 14 consecutive days, with an administration area of 200 cm ², and the prescription is shown in table 14. The control group was a commercially available soft capsule (trade name: anforda, specification 0.5 mg/granule) for oral administration of dutasteride, 1 time a day, 1 granule each time.

Table 14 0.02%, 0.06% and 0.2% gauge dutasteride alcohol-containing emulsions

The blood concentration on day one and day 14 and the content of dutasteride in skin tissue after day 14 were measured and the results are shown in table 15. It was found that the drug concentration in the dermis after topical administration of the dutasteride alcohol-containing emulsion was significantly higher than that after oral administration, and that after 14 days of administration of the 0.02% specification dutasteride alcohol-containing emulsion (0.1 mg/day), the drug concentration in the dermis was 787.5ng/g, approximately 8 times that after oral administration. This demonstrates that dutasteride in the alcohol-containing emulsion is effective in penetrating the skin barrier to the site of action and still achieves better local drug concentrations at doses of 1/5 of the oral dose. On the other hand, the blood concentration on both day 1 and day 14 of each concentration specification test group was significantly lower than that of oral administration, the daily dose (1 mg/day) of 0.02% of the dutasteride alcohol-containing emulsion was 2 times the daily dose (0.5 mg/day) of oral administration, but the area under the curve AUC _(0-t) at 14 days post administration was only 1.2% of that of oral administration. These data indicate that systemic exposure of dutasteride alcohol-containing emulsions is far lower than oral dutasteride soft capsules, and can effectively reduce toxic and side effects of dutasteride.

TABLE 15 drug distribution of different size compositions in blood of Bama piglets and skin at the site of administration

The foregoing has outlined rather broadly the more detailed description of embodiments of the invention in order that the detailed description of the principles and embodiments of the invention may be implemented in conjunction with the detailed description of embodiments of the invention that follows. Meanwhile, based on the idea of the present invention, those skilled in the art can make changes or modifications on the specific embodiments and application scope of the present invention, which belong to the protection scope of the present invention. In view of the foregoing, this description should not be construed as limiting the invention.

Claims

1. An alcoholic emulsion of a 5α-reductase inhibitor, characterized in that the alcoholic emulsion comprises a 5α-reductase inhibitor, alcohol, an oil phase, an emulsifier, a diluent and a penetration enhancer;

Wherein, in terms of weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion comprises 0.005 wt % to 0.5 wt % of a 5α-reductase inhibitor, 25 wt % to 40 wt % of alcohol, 1.3 wt % to 1.8 wt % of an oil phase, 1.0 wt % to 2.0 wt % of an emulsifier, 15 wt % to 30 wt % of a diluent, and 30 wt % to 50 wt % of a penetration enhancer;

Wherein, the 5α-reductase inhibitor is dutasteride, the alcohol is ethanol, the oil phase is white vaseline and/or white beeswax, the emulsifier is behenyl alcohol polyether and cetearyl alcohol polyether, the diluent is water, and the penetration enhancer is propylene glycol;

Wherein, the weight ratio between the alcohol, the penetration enhancer and the diluent is (25-40): (30-50): (15-30);

Wherein, the weight ratio between the oil phase and the emulsifier is 1:2~2:1;

Wherein, the hydrophilic end of the behenyl alcohol polyether contains 10-30 polyoxyethylene repeating units;

Wherein, the hydrophilic end of the cetearyl alcohol polyether contains 10-20 polyoxyethylene repeating units.

2 . The alcoholic emulsion according to claim 1 , characterized in that, based on the weight percentage of the alcoholic emulsion, the alcoholic emulsion comprises 0.01 wt % to 0.5 wt % of the 5α-reductase inhibitor.

3 . The alcoholic emulsion according to claim 2 , characterized in that, based on the weight percentage of the alcoholic emulsion, the alcoholic emulsion comprises 0.02% to 0.2% by weight of the 5α-reductase inhibitor.

The alcohol-containing emulsion according to claim 1 , wherein the ethanol is anhydrous ethanol.

5. The alcoholic emulsion according to claim 1, characterized in that, based on the weight percentage of the alcoholic emulsion, the alcoholic emulsion comprises about 33% by weight of ethanol.

6. The alcohol-containing emulsion according to claim 1, characterized in that the weight ratio between the ethanol and the diluent is not higher than (2.6~3.4): (1.6~2.4).

7. The alcoholic emulsion according to claim 1, characterized in that, based on the weight percentage of the alcoholic emulsion, the alcoholic emulsion comprises about 1.72 weight % of the oil phase.

8. The alcoholic emulsion according to claim 1, characterized in that, based on the weight percentage of the alcoholic emulsion, the alcoholic emulsion comprises about 1.6 wt% of the oil phase.

9 . The alcoholic emulsion according to claim 1 , wherein the alcoholic emulsion comprises about 1.489 wt % of the oil phase, based on the weight percentage of the alcoholic emulsion.

10. The alcohol-containing emulsion according to claim 1, characterized in that the cetearyl alcohol polyether is selected from one or more of the following: cetearyl alcohol polyether-10, cetearyl alcohol polyether-15, and cetearyl alcohol polyether-20.

11. The alcohol-containing emulsion according to claim 10, characterized in that the cetearyl alcohol polyether is cetearyl alcohol polyether-20.

12. The alcohol-containing emulsion according to claim 1, characterized in that the behenyl alcohol polyether is selected from one or more of the following: behenyl alcohol polyether-10, behenyl alcohol polyether-20, and behenyl alcohol polyether-30.

13. The alcohol-containing emulsion according to claim 12, characterized in that the behenyl alcohol polyether is behenyl alcohol polyether-30.

14. The alcohol-containing emulsion according to claim 12, characterized in that the behenyl alcohol polyether is behenyl alcohol polyether-20.

15 . The alcohol-containing emulsion according to claim 1 , characterized in that, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion comprises 1.3 wt % to 1.8 wt % of the emulsifier.

16 . The alcoholic emulsion according to claim 15 , wherein the alcoholic emulsion comprises about 1.511 wt % of the emulsifier, based on the weight percentage of the alcoholic emulsion.

17. The alcoholic emulsion according to claim 1, characterized in that, based on the weight percentage of the alcoholic emulsion, the alcoholic emulsion comprises about 1.3 wt% of the emulsifier.

18. The alcoholic emulsion according to claim 15, characterized in that, based on the weight percentage of the alcoholic emulsion, the alcoholic emulsion comprises about 1.4 weight % of the emulsifier.

19. The alcohol-containing emulsion according to claim 11, characterized in that the weight ratio between the ceteareth-20 and the beheneth-20 is 1:1 to 10:1.

20. The alcohol-containing emulsion according to claim 19, characterized in that the weight ratio between the ceteareth-20 and the beheneth-20 is 1:1 to 7:1.

21. The alcoholic emulsion according to claim 11, characterized in that, based on the weight percentage of the alcoholic emulsion, the alcoholic emulsion comprises 0.8 wt% to 1.4 wt% of ceteareth-20.

22. The alcoholic emulsion according to claim 21, characterized in that, based on the weight percentage of the alcoholic emulsion, the alcoholic emulsion comprises about 1.254 weight percent of ceteareth-20.

23. The alcoholic emulsion according to claim 21, characterized in that, based on the weight percentage of the alcoholic emulsion, the alcoholic emulsion comprises about 1.117 weight % of ceteareth-20.

24. The alcoholic emulsion according to claim 21, characterized in that, based on the weight percentage of the alcoholic emulsion, the alcoholic emulsion comprises about 1.03 weight percent of ceteareth-20.

25. The alcohol-containing emulsion according to claim 14, characterized in that, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion comprises 0.2 wt% to 0.6 wt% of beheneth-20.

26. The alcoholic emulsion according to claim 25, characterized in that, based on the weight percentage of the alcoholic emulsion, the alcoholic emulsion comprises about 0.257 weight percent of beheneth-20.

27. The alcoholic emulsion of claim 25, wherein the alcoholic emulsion comprises about 0.283 wt% of beheneth-20, based on the weight percentage of the alcoholic emulsion.

28. The alcoholic emulsion of claim 25, wherein the alcoholic emulsion comprises about 0.414 wt% of beheneth-20, based on the weight percentage of the alcoholic emulsion.

29. The alcoholic emulsion according to claim 1, characterized in that the diluent is purified water.

30. The alcoholic emulsion of claim 1, wherein the alcoholic emulsion comprises about 23% by weight of water, based on the weight percentage of the alcoholic emulsion.

31. The alcoholic emulsion of claim 1, wherein the alcoholic emulsion comprises about 40% by weight of a penetration enhancer, based on the weight percentage of the alcoholic emulsion.

32. The alcoholic emulsion of claim 1, wherein the weight ratio of the alcohol, the penetration enhancer, and the diluent is about 33: about 40: about 23.

33. The alcoholic emulsion according to claim 1, characterized in that the alcoholic emulsion further comprises other auxiliary materials.

34. The alcohol-containing emulsion according to claim 33, characterized in that the other auxiliary materials are selected from one or more of the following: a thickener, a pH regulator, an antibacterial agent and a stabilizer.

35. The alcoholic emulsion according to claim 34, characterized in that the thickener is selected from one or more of the following: carbomer, hydroxyethyl cellulose and hypromellose.

36. The alcoholic emulsion according to claim 35, wherein the carbomer is carbomer homopolymer type A.

37. The alcohol-containing emulsion according to claim 34, characterized in that, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion comprises 0.1 wt% to 0.4 wt% of a thickener.

38. The alcoholic emulsion of claim 37, wherein the alcoholic emulsion comprises about 0.3% by weight of a thickener, based on the weight percentage of the alcoholic emulsion.

39. The alcohol-containing emulsion according to claim 34, characterized in that the pH regulator is an alkaline substance.

40. The alcohol-containing emulsion according to claim 34, characterized in that the pH regulator is triethanolamine.

41. The alcohol-containing emulsion according to claim 34, characterized in that, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion comprises 0.01 wt% to 1 wt% of a pH regulator.

42. The alcohol-containing emulsion according to claim 41, characterized in that, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion comprises 0.01 wt% to 0.1 wt% of a pH regulator.

43. The alcoholic emulsion according to claim 42, characterized in that, based on the weight percentage of the alcoholic emulsion, the alcoholic emulsion comprises about 0.033 weight % of the pH adjuster.

44. The alcohol-containing emulsion according to claim 1, characterized in that, in the alcohol-containing emulsion, more than 50% of the emulsion particles have a particle size not exceeding 10 μm, and more than 90% of the emulsion particles have a particle size not exceeding 15 μm.

45. The alcohol-containing emulsion according to claim 1, characterized in that, in the alcohol-containing emulsion, more than 50% of the emulsion particles have a particle size not exceeding 5 μm, and more than 90% of the emulsion particles have a particle size not exceeding 10 μm.

46. A method for preparing the alcoholic emulsion according to any one of claims 1 to 45, characterized in that the method comprises the following steps:

(1) Weighing appropriate amounts of a 5α-reductase inhibitor, alcohol, an oil phase, an emulsifier, a diluent, and a penetration enhancer respectively, first heating and melting the oil phase and the emulsifier, and then adding the 5α-reductase inhibitor, alcohol, the diluent, and the penetration enhancer to emulsify to obtain an emulsion; and

(2) The emulsion is placed in a water bath for cooling to obtain the alcohol-containing emulsion.

47. The method according to claim 46, characterized in that the emulsification is homogeneous emulsification.

48. The method according to claim 46, characterized in that the emulsification temperature is 70°C to 90°C.

49. The method according to claim 48, characterized in that the emulsification temperature is 75°C to 85°C.

50. The method of claim 46, wherein the water bath is a cold water bath.

51. The method of claim 46, wherein the water bath is a low temperature water bath.

52. The method of claim 46, wherein the water bath is an ice water bath.

53. The method according to claim 46, characterized in that the alcoholic emulsion contains 0.01 wt% to 0.5 wt% of the 5α-reductase inhibitor, based on the weight percentage of the alcoholic emulsion.

54. The method according to claim 53, characterized in that, based on the weight percentage of the alcoholic emulsion, the alcoholic emulsion contains 0.02 wt% to 0.2 wt% of the 5α-reductase inhibitor.

55. The method of claim 46, wherein the ethanol is anhydrous ethanol.

56. The method of claim 46, wherein the alcoholic emulsion comprises about 33% ethanol by weight of the alcoholic emulsion.

57. The method of claim 46, wherein the weight ratio of the ethanol to the diluent is no greater than (2.6-3.4): (1.6-2.4).

58. The method of claim 46, wherein the alcoholic emulsion comprises about 1.72 weight percent oil phase, based on the weight percent of the alcoholic emulsion.

59. The method of claim 46, wherein the alcoholic emulsion comprises about 1.6 wt% oil phase, based on the weight percentage of the alcoholic emulsion.

60. The method of claim 46, wherein the alcoholic emulsion comprises about 1.489 wt% oil phase, based on the weight percentage of the alcoholic emulsion.

61. The method according to claim 46, characterized in that the emulsifier is behenyl alcohol polyether and cetearyl alcohol polyether, the hydrophilic end of the behenyl alcohol polyether contains 10-30 polyoxyethylene repeating units, and the hydrophilic end of the cetearyl alcohol polyether contains 10-20 polyoxyethylene repeating units.

62. The method according to claim 61, characterized in that the ceteareth is selected from one or more of the following: ceteareth-10, ceteareth-15, and ceteareth-20.

63. The method according to claim 61, characterized in that the ceteareth is ceteareth-20.

64. The method according to claim 61, characterized in that the beheneth is beheneth-10, beheneth-20 and/or beheneth-30.

65. The method of claim 61, wherein the beheneth is beheneth-30.

66. The method of claim 61, wherein the beheneth is beheneth-20.

67. The method according to claim 46, characterized in that, based on the weight percentage of the alcoholic emulsion, the alcoholic emulsion contains 1.3 wt% to 1.8 wt% of the emulsifier.

68. The method of claim 67, wherein the alcoholic emulsion comprises about 1.511 wt% emulsifier, based on the weight percentage of the alcoholic emulsion.

69. The method of claim 46, wherein the alcoholic emulsion comprises about 1.3 wt% emulsifier, based on the weight percentage of the alcoholic emulsion.

70. The method of claim 67, wherein the alcoholic emulsion comprises about 1.4 weight percent emulsifier, based on the weight percent of the alcoholic emulsion.

71. The method according to claim 46, characterized in that the weight ratio between the oil phase and the emulsifier is 1:2 to 5:1.

72. The method according to claim 71, characterized in that the weight ratio between the oil phase and the emulsifier is 1:2 to 2:1.

73. The method according to claim 63, characterized in that the weight ratio between the ceteareth-20 and beheneth-20 is 1:1 to 10:1.

74. The method according to claim 73, characterized in that the weight ratio between the ceteareth-20 and the beheneth-20 is 1:1 to 7:1.

75. The method of claim 63, wherein the alcoholic emulsion comprises 0.8 wt% to 1.4 wt% of ceteareth-20, based on the weight percentage of the alcoholic emulsion.

76. The method of claim 75, wherein the alcoholic emulsion comprises about 1.254 weight percent ceteareth-20, based on the weight percent of the alcoholic emulsion.

77. The method of claim 75, wherein the alcoholic emulsion comprises about 1.117 weight percent ceteareth-20, based on the weight percent of the alcoholic emulsion.

78. The method of claim 75, wherein the alcoholic emulsion comprises about 1.03% by weight of ceteareth-20, based on the weight percentage of the alcoholic emulsion.

79. The method of claim 66, wherein the alcoholic emulsion comprises 0.2 wt % to 0.6 wt % of beheneth-20, based on the weight percentage of the alcoholic emulsion.

80. The method of claim 79, wherein the alcoholic emulsion comprises about 0.257 weight percent beheneth-20, based on the weight percent of the alcoholic emulsion.

81. The method of claim 79, wherein the alcoholic emulsion comprises about 0.283 wt % beheneth-20, based on the weight percentage of the alcoholic emulsion.

82. The method of claim 79, wherein the alcoholic emulsion comprises about 0.414 weight percent beheneth-20, based on the weight percent of the alcoholic emulsion.

83. The method of claim 46, wherein the diluent is purified water.

84. The method of claim 83, wherein the alcoholic emulsion comprises about 23% by weight of purified water, based on the weight percentage of the alcoholic emulsion.

85. The method of claim 46, wherein the alcoholic emulsion comprises about 40% by weight of the penetration enhancer, based on the weight percentage of the alcoholic emulsion.

86. The method of claim 46, wherein the weight ratio between the alcohol, the penetration enhancer, and the diluent is about 33: about 40: about 23.

87. The method according to claim 46, characterized in that, in step (1), it further comprises the step of weighing appropriate amounts of other auxiliary materials.

88. The method according to claim 46, characterized in that, in step (2), it further comprises the step of adding other auxiliary materials and mixing them.

89. The method according to claim 87 or 88, characterized in that the other auxiliary materials are selected from one or more of the following: a thickener, a pH regulator, an antibacterial agent and a stabilizer.

90. The method of claim 89, wherein the thickening agent is selected from one or more of the following: carbomer, hydroxyethyl cellulose, and hypromellose.

91. The method of claim 90, wherein the carbomer is carbomer homopolymer type A.

92. The method according to claim 89, characterized in that the alcoholic emulsion comprises 0.1 wt% to 0.4 wt% of a thickener, based on the weight percentage of the alcoholic emulsion.

93. The method of claim 92, wherein the alcoholic emulsion comprises about 0.3% thickener by weight of the alcoholic emulsion.

94. The method according to claim 89, characterized in that the pH adjuster is an alkaline substance.

95. The method of claim 89, wherein the pH adjusting agent is triethanolamine.

96. The method according to claim 89, characterized in that, based on the weight percentage of the alcoholic emulsion, the alcoholic emulsion contains 0.01 wt% to 1 wt% of a pH adjuster.

97. The method according to claim 96, characterized in that, based on the weight percentage of the alcoholic emulsion, the alcoholic emulsion contains 0.01 wt% to 0.1 wt% of a pH adjuster.

98. The method of claim 97, wherein the alcoholic emulsion comprises about 0.033 wt % of a pH adjuster, based on the weight percentage of the alcoholic emulsion.

99. The method according to claim 46, characterized in that, in the alcohol-containing emulsion, more than 50% of the emulsion particles have a particle size not exceeding 10 μm, and more than 90% of the emulsion particles have a particle size not exceeding 15 μm.

100. The method according to claim 46, characterized in that, in the alcohol-containing emulsion, more than 50% of the emulsion particles have a particle size not exceeding 5 µm, and more than 90% of the emulsion particles have a particle size not exceeding 10 µm.